Analysis of the activity-deprived zebrafish mutant macho reveals an essential requirement of neuronal activity for the development of a fine-grained visuotopic map.

The formation of a retinotopic map is thought to involve an activity-independent molecular phase for early steps of both axon pathfinding and projection and a later phase in which cross talk between retinal ganglion cells (RGCs) and tectal neurons modifies and refines the neuronal connections. We report that the maturation of the retinotopic map in the zebrafish tectum involves activity-dependent processes. Zebrafish larvae mutant for the gene macho (mao) lack neuronal activity in RGCs and also display an enlarged retinotectal projection field but no significant increase in single axon length. This morphological defect can be phenocopied by raising larvae under TTX-induced neural impulse blockade. The effect of activity deprivation is dependent on the developmental stage. The projection phenotype in mao as well as in the TTX-treated larvae develops between 4 and 6 d post-fertilization (dpf), after complete tectal coverage is first achieved. Electrophysiological recordings of RGCs in wild-type and mao zebrafish larvae reveal a temporally regulated reduction of sodium current in the mutant between 5 and 6 dpf. This coincides with the time of the axonal projection shifting on the tectum to compensate for the disparate growth patterns of the retina and the tectum. Our genetic and physiological analyses suggest a model in which neuronal activity in RGCs is needed for the establishment of morphological plasticity

A Multi-Component Model of the Developing Retinocollicular Pathway Incorporating Axonal and Synaptic Growth

During development, neurons extend axons to different brain areas and produce stereotypical patterns of connections. The mechanisms underlying this process have been intensively studied in the visual system, where retinal neurons form retinotopic maps in the thalamus and superior colliculus. The mechanisms active in map formation include molecular guidance cues, trophic factor release, spontaneous neural activity, spike-timing dependent plasticity (STDP), synapse creation and retraction, and axon growth, branching and retraction. To investigate how these mechanisms interact, a multi-component model of the developing retinocollicular pathway was produced based on phenomenological approximations of each of these mechanisms. Core assumptions of the model were that the probabilities of axonal branching and synaptic growth are highest where the combined influences of chemoaffinity and trophic factor cues are highest, and that activity-dependent release of trophic factors acts to stabilize synapses. Based on these behaviors, model axons produced morphologically realistic growth patterns and projected to retinotopically correct locations in the colliculus. Findings of the model include that STDP, gradient detection by axonal growth cones and lateral connectivity among collicular neurons were not necessary for refinement, and that the instructive cues for axonal growth appear to be mediated first by molecular guidance and then by neural activity. Although complex, the model appears to be insensitive to variations in how the component developmental mechanisms are implemented. Activity, molecular guidance and the growth and retraction of axons and synapses are common features of neural development, and the findings of this study may have relevance beyond organization in the retinocollicular pathway

Analysis of the Activity-Deprived Zebrafish Mutant macho

The formation of a retinotopic map is thought to involve an activity-independent molecular phase for early steps of both axon pathfinding and projection and a later phase in which cross talk between retinal ganglion cells (RGCs) and tectal neurons modifies and refines the neuronal connections. We report that the maturation of the retinotopic map in the zebrafish tectum involves activity-dependent processes. Zebrafish larvae mutant for the gene macho (mao) lack neuronal activity in RGCs and also display an enlarged retinotectal projection field but no significant increase in single axon length. This morphological defect can be phenocopied by raising larvae under TTX-induced neural impulse blockade. The effect of activity deprivation is dependent on the developmental stage. The projection phenotype in mao as well as in the TTX-treated larvae develops between 4 and 6 d post-fertilization (dpf), after complete tectal coverage is first achieved. Electrophysiological recordings of RGCs in wild-type and mao zebrafish larvae reveal a temporally regulated reduction of sodium current in the mutant between 5 and 6 dpf. This coincides with the time of the axonal projection shifting on the tectum to compensate for the disparate growth patterns of the retina and the tectum. Our genetic and physiological analyses suggest a model in which neuronal activity in RGCs is needed for the establishment of morphological plasticity